The identification, description, and treatment of congenital and acquired syndromes of increased susceptibility to infection primarily affecting the phagocytes, especially those related to nontuberculous mycobacteria have been our focus. These organisms are important pathogens only in the immunocompromised host, so we have sought to identify patients without recognized forms of immunocompromise who have these infections and then determine the nature of their susceptibility. In this way we can identify novel pathways involved in the control of mycobacteria and potentially other intracellular pathogens. We have identified several discrete abnormalities in these patients, all of which center around macrophage/lymphocyte interactions leading to the production of interferon gamma. The study of these "experiments of nature" highlights the critical role of the macrophage/lymphocyte interaction in control of mycobacteria and has led to the development of novel therapies that may have important applications in the most deadly infectious disease, tuberculosis.